In vivo assessment of substrate utilisation in the hypertrophied heart; the role of glycolysis and glucose oxidation in hypertrophic progression

The work in this thesis investigates the role of glycolysis and glucose oxidation and the effects of metabolic modulation on the development of left ventricular hypertrophy (LVH) in the abdominal aortic constriction (AC) model. Hypertrophy was induced via the surgical constriction of the abdominal aorta (AC) and through the combined use of cine MRI and dynamic nuclear polarization (DNP), hypertrophic development and progression was assessed. A 17 % increase in LV mass was observed within the AC group at 4, 9 and 14 weeks post-surgery accompanied by no evidence of functional decline. Increased incorporation into lactate was observed at 4 and 9 weeks post-surgery representative of enhanced glycolytic dependence. Increase glycolytic flux was confirmed in the isolated Langendorff-perfused heart at 10 weeks post-surgery. No metabolic changes were observed in vivo at 14 weeks post-surgery accompanied by no change in glycolytic flux in the perfused heart at 18 weeks post-surgery. Treatment of the AC model with dichloroacetate (DCA; 0.75 g L-1) was associated with an elevation in pyruvate dehydrogenase (PDH) flux as expected. When treatment was given immediately post-surgery, a significant increase in LV mass was observed at 4 (23 %), 9 (27 %) and 14 (24 %) weeks post-surgery accompanied by functional decline at 4 and 9 weeks post-surgery. However, treatment of the AC model with DCA at 5 weeks post- surgery, following the establishment of hypertrophy, was associated with no significant difference in LV mass (12 % increase) at 9 weeks post-surgery, however an elevation in LV mass was still present at 14 weeks post-surgery and no functional decline was observed. Treatment with either a low dose (0.1 mg kg-1 day-1) or high dose (1 mg kg-1 day-1) of Ramipril at 5 weeks post-surgery, following the development hypertrophy, was associated with a normalisation of LV mass in the treated groups but was not associated with any metabolic changes. This work clarifies the structural, functional and metabolic changes which occur during hypertrophic development and progression as well as the effects of different metabolic therapies. It highlights the potential of the combined use of DNP and cine MRI to further understand hypertrophic progression in patients and the effects of different therapies.